JPH10139660A - Water-soluble azulene pharmaceutical preparation and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce the subject pharmaceutical preparation capable of retaining the stability for a longer period and formulating a carboxyvinyl polymer in an amount of >2.0% by including a water-soluble azulene, a nonionic surfactant, etc., therein. SOLUTION: This pharmaceutical preparation comprises (A) 0.01-2.5wt.% water-soluble azulene, (B) a nonionic surfactant, (C) 0.005-0.50wt.% soybean phospholipid and (D) a petroleum-based hydrocarbon, (E) gelatin, (F) 5-20wt.% ethanol, (G) 30-50wt.% polyhydric alcohol, (H) 2.1-4.0wt.% carboxyvinyl polymer and (I) 1.0-5.0wt.% water-soluble polymer. The objective pharmaceutical preparation is produced by formulating the ingredient A with the ingredient B, dispersing the resultant formulation in the ingredient D containing the ingredients C and B formulated in the ingredient D and formulating the prepared dispersion in a biological tissue adhesive base containing the ingredients E, F, G, H and I therein.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a water-soluble azulene preparation capable of maintaining long-term stability, and a method for producing the same.

[0002]

2. Description of the Related Art Water-soluble azulene is widely used as an important drug, and has been used as a remedy for gastritis, ulcer, stomatitis and pharyngitis due to having an anti-inflammatory effect and an epithelial formation promoting effect. I have. In addition, in the ophthalmology field, it is used for allergic conjunctivitis and blepharitis because it has an antiallergic effect, and it is also used as an oral agent such as a mouthwash.In recent years, it has been used in the field of quasi drugs. Used for brushing teeth.

[0003] However, the water-soluble azulene is a dark blue crystal and easily soluble in water, and is unstable to heat and light. Therefore, when stored at room temperature, the color gradually fades and decomposes into guaiazulene. The aqueous solution is relatively stable under weak alkaline conditions, but has a pH of 5 or less.
It has the property of decomposing rapidly when it becomes acidic below.

Therefore, for the purpose of suppressing the decomposition of such water-soluble azulene, for example, JP-A-7-898
A carboxyvinyl polymer gel preparation containing a water-soluble azulene as described in JP-B-50 is proposed. An object of the present invention is to provide a water-soluble azulene preparation capable of obtaining a homogeneous preparation and maintaining long-term stability, and a method for producing the same. This formulation can provide an appropriate viscosity by being mixed with a cream base, a gel base, and an ointment base, and particularly when expected to adhere to living tissues, it can be used as a gel base. The use of known carboxyvinyl polymers may be appropriate.

Heretofore, several preparations to which a carboxyvinyl polymer is applied have been invented, and examples of application to oral preparations are disclosed in JP-A-7-267839 (i) and JP-A-7-126133 (ii). The carboxyvinyl polymer has a compounding amount of 2.0 or 10.0% or less, respectively, and is excellent in ductility, adhesion, penetration force, and penetrating power to the oral mucosa. In the latter case, in particular, by blending a non-steroidal anti-inflammatory agent, even if the carboxyvinyl polymer is blended at a high concentration, the preparation is excellent in ductility.

[0006]

However, (i)
Means that if the compounding amount of the carboxyvinyl polymer exceeds 2.0%, the ductility is poor and the object of the invention cannot be achieved. However, when actually used, there is a problem that it is not possible to feel the adhesion to the oral mucosa. (I
In i), in order to provide a product with excellent ductility, the combination of a nonsteroidal anti-inflammatory drug and hydroxypropyl methylcellulose is essential, and in this case, it cannot be applied to quasi-drugs and cosmetics other than pharmaceuticals. There is.

Further, Japanese Patent Application Laid-Open No.
The invention described in Japanese Patent No. 89850 is applied as an external preparation such as a cream, a gel, an ointment or the like.
There is a problem that expected effects cannot be obtained.

Accordingly, the present invention provides a water-soluble azulene having more long-term stability and a carboxyvinyl polymer content of more than 2.0%. And soybean phospholipids are blended, so it is excellent in spreadability, and there is no restriction on the drugs to be blended, so in pharmaceuticals, quasi-drugs or cosmetics, etc. An object of the present invention is to provide a water-soluble azulene formulation comprising a gel base which can be freely blended and a method for producing the same.

[0009]

Accordingly, the water-soluble azulene preparation of the present invention comprises water-soluble azulene, a nonionic surfactant, soybean phospholipid, petroleum hydrocarbon, gelatin, ethanol, polyhydric alcohol, carboxy A biological tissue-adhesive base containing a vinyl polymer and a water-soluble polymer is blended.

The water-soluble azulene preparation of the present invention comprises
0.01 to 2.5% by weight of the water-soluble azulene, 0.005 to 0.50% by weight of soybean phospholipid, 5 to 20% by weight of ethanol, The compounding amount is 30 to 50% by weight, the compounding amount of the carboxyvinyl polymer is 2.1 to 4.0% by weight, and the compounding amount of the water-soluble polymer is 1.0 to 5.0% by weight. it can.

Further, the method for producing a water-soluble azulene preparation of the present invention comprises a step of mixing a water-soluble azulene with a non-ionic surfactant, and mixing the resulting mixture with a soybean phospholipid and a non-ionic surfactant. The dispersion in hydrogen is further blended with a biological tissue-adhesive base containing gelatin, ethanol, polyhydric alcohol, carboxyvinyl polymer, and a water-soluble polymer.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The water-soluble azulene preparation of the present invention comprises
It is manufactured as follows.

First, water-soluble azulene is mixed with a nonionic surfactant and dispersed in petroleum hydrocarbon. In this case, it is preferable to use a nonionic surfactant having an HLB of 14 or more. It is not preferable to use one having an HLB of less than 14, since stable dispersion of water-soluble azulene in petroleum hydrocarbons by surfactant micelles cannot be expected. The amount of the water-soluble azulene is preferably 0.01 to 2.5% by weight, more preferably 0.035 to 0.05% by weight, based on the nonionic surfactant.

The petroleum hydrocarbon is previously blended with a nonionic surfactant of HLB 3-9 and soybean phospholipid.
In this case, it is not preferable to use a compound having an HLB of less than 3 or a compound having an HLB of more than 9 because the surfactant micelle of water-soluble azulene contained in petroleum hydrocarbons is aggregated. Soybean phospholipids are mainly composed of components such as phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol. Is done. The compounding amount is 0.005 to 0.5 with respect to the total amount of the preparation.
The content is preferably 50% by weight, and more preferably 0.01 to 0.1%.
More preferably, the content is 10% by weight.

Then, the petroleum hydrocarbon in which the water-soluble azulene is dispersed is mixed with a biological tissue-adhering base containing gelatin, ethanol, a polyhydric alcohol, a carboxyvinyl polymer, and a water-soluble polymer. Stabilize.

The nonionic surfactant according to the present invention comprises:
Polyoxyethylene hydrogenated castor oil (PEHC), polyoxyethylene stearyl ether (PESE), polyoxyethylene sorbitan fatty acid ester (PESF),
A member selected from the group consisting of polyoxyethylene alkyl ether (PEAE), glycerin fatty acid ester (MSG), polyethylene glycol monostearate (MSPG), sorbitan fatty acid ester (SF), and polyoxyethylene polyoxypropylene alkyl ether (PPAE). Two or more types are used, and HLB 3 to 9 or HLB 14 or more are selected from the above and blended. The compounding amount based on the total amount of the preparation is preferably 0.5 to 5.0% by weight, and more preferably 1.0 to 2.0% by weight. When the amount of the nonionic surfactant increases, the effectiveness of the azulene preparation decreases, so that the amount exceeding 5.0% by weight is not preferable. Also,
If the amount is less than 0.5% by weight, formation of an emulsion of petroleum hydrocarbons is not sufficiently performed, which is not preferable.

The petroleum hydrocarbons include liquid paraffin, solid paraffin, microcrystalline wax,
One or more selected from petrolatum or the like is used, and the amount contained in the total amount of the preparation is preferably 0.5 to 12.0% by weight, and more preferably 1.0 to 5.0% by weight. More preferably,

The polyhydric alcohol has two or more hydroxyl groups in the molecule and includes, for example, glycerin, propylene glycol, erythritol and concentrated glycerin. Among them, concentrated glycerin is preferably used from polyhydric alcohols. You. The compounding amount is 3 to the total amount of the preparation.
The content is preferably 0 to 50% by weight, and more preferably 35 to 45% by weight.
More preferably, the percentage is by weight.

Gelatin can be used widely from low molecular weight to high molecular weight, and among them, low molecular weight water-soluble gelatin is preferably used. The amount of gelatin is 0.1 to 1.0% by weight, preferably 0.2 to 0.5% by weight, based on the total amount of the preparation. The compounding is preferably performed in the state of an aqueous solution.

As the water-soluble polymer, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose and the like are used, and among them, hydroxypropylcellulose is preferably used. The compounding amount is preferably 1.0 to 5.0% by weight, more preferably 3.0 to 4.0% by weight, based on the total amount of the preparation.

As the carboxyvinyl polymer, 0.1.
A 5% neutralized solution having a viscosity of 3,000 to 80,000 can be used, of which 30,000 is used.
It is preferred to use those which are up to 60,000. The compounding amount is preferably 2.1 to 4.0% by weight, and more preferably 2.5 to 3.0% by weight, based on the total amount of the preparation.

As the neutralizing agent, sodium hydroxide or the like is used, and the ductility is controlled by the ethanol and the soybean phospholipid. Ethanol content is 5-20% by weight
And more preferably 10 to 13% by weight.

These biological tissue-adhesive bases are formulated for the purpose of forming and stabilizing an emulsion of petroleum hydrocarbons. In particular, the addition of gelatin to a pharmaceutical preparation contributes to the stabilization of water-soluble azulene. I do. The amount of each is
There is no restriction at all if it is set within a range where uniform dispersion of petroleum hydrocarbons is possible.

In addition, if necessary, sequestering agents (EDTA), inorganic salts and the like can be blended within a range that does not impair the effects of the present invention.

Therefore, the water-soluble azulene preparation of the present invention
Contains water-soluble azulene, non-ionic surfactant, soybean phospholipid, petroleum hydrocarbon, and biotissue-adhesive base containing gelatin, ethanol, polyhydric alcohol, carboxyvinyl polymer, and water-soluble polymer It is assumed to be. And the water-soluble azulene preparation of the present invention,
Gels, creams, ointments can be prepared,
Because of its excellent ductility, oral mucosa adhesion, and skin adhesive properties, it can be applied to external medicines for skin diseases and external periodontal disease treatment in the field of pharmaceuticals.
It can be used when disinfection, repair, protection, anti-inflammatory action, improvement of dry skin and antipruritic action are expected. In addition, in the field of quasi-drugs or cosmetics, it can be used according to the application such as hand cream or cosmetic cream for preventing rough skin.

[0026]

The present invention will be described below in more detail with reference to examples. (Preparation of Examples 1 to 4) According to the compounding amount shown in Table 1, a nonionic surfactant having an HLB of 14 or more is heated and melted, and a water-soluble azulene is compounded. A soybean phospholipid and a nonionic surfactant in the range of HLB 3 to 9 are heated and melted in a mixture of liquid paraffin, which is a petroleum hydrocarbon, and microcrystalline wax or vaseline or solid paraffin. A non-ionic surfactant micelle of water-soluble azulene is formed.

[0027] According to the compounding amount shown in Table 1, an aqueous solution in which gelatin and other water-soluble bases are dissolved, and ethanol in which a nonionic surfactant having an HLB of 14 or more is added to glycerin, mixed, stirred, and the carboxyvinyl polymer is added thereto. Mix and disperse. Then, after neutralizing with an aqueous solution in which sodium hydroxide is dissolved, a water-soluble polymer is blended and mixed and stirred.

[0028] To prepare a water-in-oil type emulsion to prepare a 100 g water-soluble azulene formulation.

(Preparation method of Comparative Examples 1 to 4) In accordance with the compounding amounts shown in Table 2, preparations are made by the same preparation method as in the examples. However,
Comparative Examples 3 and 4 do not contain petroleum hydrocarbons, gelatin and hydroxypropylcellulose. Comparative Examples 1-4 do not contain ethanol and soybean phospholipids.

[0030]

[Table 1]

[0031]

[Table 2]

Next, with respect to Example 1 and Comparative Example 1, the content (%) of water-soluble azulene in the preparations subjected to the accelerated test (environmental temperature: 40 ° C.) was measured over time. Table 3 shows the results. As is evident from Table 3, the water-soluble azulene preparation of the present invention hardly decomposes after 6 months under the accelerated test, and can maintain even longer-term stability by blending ethanol and soybean phospholipid. Was confirmed.

[0033]

[Table 3]

Further, in Examples 1 and 2 and Comparative Examples 1 and 2, a usability survey was conducted on human oral mucosa for ease of application, adhesion to living tissue, and bending ductility. The ease of application was evaluated by a three-stage evaluation of easy application and difficult feeling of application. The evaluation of the adhesion to the living tissue was performed on a five-point scale of very strong, strong, neither, weak, or very weak. Further, the evaluation of ductility was made into a four-point scale of very good, good, bad, and very bad.

As a result, as shown in Table 4, ethanol,
Even if the carboxyvinyl polymer is added in an amount exceeding 2.0% by weight, the application of soybean phospholipids makes it easy to apply, and Table 5 confirms that the adhesiveness to living tissues and the ductility are excellent.

[0036]

[Table 4]

[0037]

[Table 5]

[0038]

Since the water-soluble azulene preparation of the present invention is constituted as described above, it is possible to maintain long-term stability, and also to have a ductility and an adhesive force at the application site of the preparation. As a result, the use feeling was excellent.

The water-soluble azulene preparation of the present invention
When treating various injuries in the field of pharmaceuticals, it can be expected that the affected area can be treated more effectively, and it can be applied to cosmetics and quasi-drugs. Furthermore, there is an effect that sufficient quality assurance can be performed without quality deterioration in the market distribution process, the manufacturing method is relatively simple, the manufacturing process is not complicated, and no large equipment is required.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Taketoshi Shinnobu 2-76-7 Sukukusho, Ibaraki-shi, Osaka Tanpei Pharmaceutical Co., Ltd.

Claims (3)

[Claims] 1. A living tissue adhering containing water-soluble azulene, a nonionic surfactant, soybean phospholipid, petroleum hydrocarbon, and gelatin, ethanol, polyhydric alcohol, carboxyvinyl polymer, and water-soluble polymer. A water-soluble azulene preparation characterized by comprising an acidic base. 2. The compounding amount of the water-soluble azulene is 0.01
~ 2.5 wt%, soybean phospholipid blending amount 0.005 ~
0.50% by weight, 5-20% by weight of ethanol, 30-50% by weight of polyhydric alcohol, 2.1-4.0% by weight of carboxyvinyl polymer, high water solubility The water-soluble azulene preparation according to claim 1, wherein the amount of the molecule is 1.0 to 5.0% by weight. 3. A water-soluble azulene compounded in a nonionic surfactant, which is dispersed in a soybean phospholipid and a petroleum hydrocarbon mixed with a nonionic surfactant,
A method for producing a water-soluble azulene preparation, which is further blended with a living tissue-adhering base containing gelatin, ethanol, polyhydric alcohol, carboxyvinyl polymer and water-soluble polymer.